Non-insulin-dependent diabetes mellitus (NIDDM, Type 2 diabetes, maturity onset diabetes) is one of the most common chronic disorders in our population. Despite considerable study, the etiological origins of the disorder remain obscure. A large body of evidence indicates a prominent genetic component in susceptibility to NiDDM, making it an appropriate subject for genetic analysis. The suitability of such an approach has been demonstrated by the discovery of linkage between polymorphic markers on chromosome 20 and a form of NIDDM called maturity onset diabetes of the young (MODY). The goal of this work is to identify the MODY gene on chromosome 20 using molecular biology and genetic techniques and approaches. This goal is being approached in several ways: (l) Genetic techniques will be used to better define the position of the MODY gene on chromosome 20. This will include evaluating the role of several candidate genes in the region. This genetic analysis will be coupled with (2) physical mapping techniques to map the MODY locus to a smaller physical/genetic region (approximately l cM; approximately l megabase) as a prerequisite for identifying candidate gene sequences and the search for potential mutagenic deletions or rearrangements of the genomic DNA. isolation of additional markers on 20q will be the basis of genetic mapping and will be coupled with a search for yeast artificial chromosomes (YACs) containing-these loci. YAC chromosome walking will be carried out to clone the chromosome 20 genomic fragments containing the MODY gene. Coding sequences in these clones will be identified through a variety of approaches and evaluated for the possibility that they are involved in MODY.